反应详情

A mixture of (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 10.1, 119 mg, 0.25 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (139 mg, 0.5 mmol), Pd(PPh3)2Cl2 (0.018 g, 0.025 mmol), Na2CO3 (0.106 g, 1.000 mmol), DME (1.061 mL), water (0.303 mL) and EtOH (0.152 mL) were added to a MW vial which was sealed, evacuated/purged 3 times with argon then subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with DME (2 mL) and stirred overnight with Si-Thiol (Silicycle 1.43 mmol/g, 0.105 g, 0.150 mmol). The mixture was centrifuged and the supernatant was filtered through a 0.45 μm PTFE filter and the solvent was evaporated off under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 20% to 90% EtOAc) to afford the protected intermediate which was treated with a mixture of DCM (2.5 mL) and TFA (0.963 mL, 12.50 mmol) and stirred at RT for 2 h. The solvent was evaporated off under reduced pressure and the residue treated with a solution of 7 N NH3 in MeOH (2 mL, 14 mmol). The solvent was evaporated off under reduced pressure and the residue was purified by preparative SFC (Column DEAP, isocratic 28% in 9 min) to afford the title compound as a yellow oil. UPLC-MS (Condition 1) tR=1.87 min, m/z=464.1 [M+H]+, m/z=462.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.65 (m, 1H) 1.75-1.97 (m, 1H) 2.14-2.30 (m, 1H) 3.04 (dd, J=11.37, 6.97 Hz, 1H) 3.14-3.26 (m, 2H) 3.26-3.29 (m, 1H) 3.35-3.46 (m, 2H) 4.60 (t, J=5.14 Hz, 1H) 6.39 (d, J=1.96 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.76 (br. s, 1H) 7.84-7.94 (m, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.74 (s, 1H) 10.18 (s, 1H) 12.87 (br. s, 1H).

1. additionwere added to a MW vial which
2. customwas sealed
3. customevacuated/purged 3 times with argon
4. customthen subjected to MW irradiation at 125° C. for 20 min
5. additionThe RM was diluted with DME (2 mL)
6. filtrationthe supernatant was filtered through a 0.45 μm PTFE
7. filtrationfilter
8. customthe solvent was evaporated off under reduced pressure
9. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 20% to 90% EtOAc)
10. customto afford the protected intermediate which
11. customThe solvent was evaporated off under reduced pressure
12. customThe solvent was evaporated off under reduced pressure
13. customthe residue was purified by preparative SFC (Column DEAP, isocratic 28% in 9 min)